Coatings with tunable molecular architecture for drug-coated balloon

ABSTRACT

A drug delivery balloon is provided, the a balloon having an outer surface, and a tunable coating disposed on at least a length of the balloon surface. The tunable coating includes a first therapeutic agent and a first excipient, and can include a second therapeutic agent and a second excipient. The first and second therapeutic agents have different dissolution rates during balloon inflation and therefore provide a coating that is tunable.

FIELD OF THE INVENTION

The disclosed subject matter is related to the delivery of drugs from aninsertable medical device. More particularly, the disclosed subjectmatter relates to a medical device including a balloon for delivery of atherapeutic agent, the balloon having a tunable, durable coatingdisposed on its outer surface.

BACKGROUND OF THE INVENTION

Atherosclerosis is a syndrome affecting arterial blood vessels. Ahallmark of atherosclerosis is a chronic inflammatory response in thewalls of arteries, in large part due to the accumulation of lipid,cholesterol, leucocytes, and other inflammatory cells and the formationof plaque on the arterial wall. Atherosclerosis is commonly referred toas hardening of the arteries. Angioplasty is a vascular interventionaltechnique involving mechanically widening an obstructed blood vessel,typically caused by atherosclerosis.

During angioplasty, a catheter having a tightly folded balloon isinserted into the vasculature of the patient and is passed to thenarrowed location of the blood vessel at which point the balloon isinflated to a fixed size using an inflation fluid, typicallyangiographic contrast media. Percutaneous coronary intervention (PCI),commonly known as coronary angioplasty, is a therapeutic procedure totreat the stenotic coronary arteries of the heart, often found incoronary heart disease.

In contrast, peripheral angioplasty, commonly known as percutaneoustransluminal angioplasty (PTA), refers to the use of mechanical wideningof blood vessels other than the coronary arteries. PTA is most commonlyused to treat narrowing of the leg arteries, especially, the iliac,external iliac, superficial femoral and popliteal arteries. PTA can alsotreat narrowing of veins, and other blood vessels.

Although the blood vessel is often successfully widened by angioplasty,sometimes the treated wall of the blood vessel experienced abruptclosure after balloon inflation or dilatation due to acute recoil orvasospasm. One solution to such collapse is stenting the blood vessel toprevent collapse. A stent is a device, typically a metal tube orscaffold, that is inserted into the blood vessel following angioplasty,in order to hold the blood vessel open.

While the advent of stents eliminated many of the complications ofabrupt vessel closure after angioplasty procedures, within about sixmonths of stenting, a re-narrowing of the blood vessel can form, acondition known as restenosis. Restenosis was discovered to be aresponse to the injury of the angioplasty procedure and is characterizedby a growth of smooth muscle cells—analogous to a scar forming over aninjury. As a solution, drug eluting stents were developed to address thereoccurrence of the narrowing of blood vessels. One example of a drugeluting stent is a metal stent that has been coated with a drug that isknown to interfere with the process of restenosis. A potential drawbackof certain drug eluting stents is known as late stent thrombosis, whichis an event in which blood clots inside the stent.

Drug eluting balloons are believed to be a viable alternative to drugeluting stents in the treatment of atherosclerosis. In a study whichevaluated restenosis and the rate of major adverse cardiac events suchas heart attack, bypass, repeat stenosis, or death in patients treatedwith drug eluting balloons and drug eluting stents, the patients treatedwith drug eluting balloons experienced only 3.7 percent restenosis and4.8% MACE (major adverse coronary events) as compared to patientstreated with drug eluting stents, in which restenosis was 20.8 percentand 22.0 percent MACE rate. (See, PEPCAD II study, Rotenburg, Germany).

Although drug eluting balloons are a viable alternative, and in somecases appear to have greater efficacy than drug eluting stents assuggested by the PEPCAD II study, drug eluting balloons presentchallenges due to the very short period of contact between the drugcoated balloon surface and the blood vessel wall. In particular, theballoon can only be inflated for less than one minute, and is ofteninflated for only thirty seconds. Therefore, an efficacious, therapeuticamount of drug must be transferred to the vessel wall within athirty-second to one-minute time period. For the peripheral vasculature,the allowable inflation times can be greater than one minute, but arestill measured in minutes. Thus, there are challenges specific to drugdelivery via a drug coated balloon because of the necessity of a shortinflation time, and therefore time for drug or coating transfer—achallenge not presented by a drug eluting stent, which remains in thepatient's vasculature once implanted.

Other considerations are the current theories about the mechanism bywhich a drug coated balloon transfers drug to the vessel wall. Onetheory, for example, is that upon balloon expansion, drug mechanicallyfractures or dissolves from the coating, diffuses to the vessel wall andthen permeates into the vessel wall. A second theory is that uponballoon expansion the balloon coating is transferred to the vessel wall,and then drug permeates into the vessel wall from the coating adhered tothe vessel wall. Another theory is that the balloon expansion createstears and microfissures in the vessel wall, and a portion of the coatinginserts into the tears and microfissures. Drug then permeates into thevessel wall from the coating within the tears and fissures. Yet anothertheory is that upon balloon expansion, a layer of dissolved drug andcoating excipients is formed at a high concentration on the vessel wallas a boundary layer. The drug diffuses and permeates from this boundarylayer into the vessel wall. In most of these theories, the drugtransfers from the balloon to the circulation or the vascular walltissue upon fracture of the coating due to inflation of the balloon andoccurs within one minute, and preferably within 30 seconds. Therefore, aneed exists for a drug coated balloon having efficient drug transfer toa vessel wall.

Various embodiments of drug-coated balloons have been proposed,including balloons with a therapeutic agent disposed directly on theballoon surface and balloons having various protective sheaths. However,not all embodiments result in an efficacious response in reducingrestenosis after balloon and bare metal stent trauma.

Therefore, a need exists for a drug eluting balloon and moreparticularly, a balloon coated with a therapeutic agent that providesfor effective delivery kinetics of the therapeutic agent from thesurface of the balloon.

SUMMARY OF INVENTION

The purpose and advantages of the disclosed subject matter will be setforth in and apparent from the description that follows, as well as willbe learned by practice of the disclosed subject matter. Additionaladvantages of the disclosed subject matter will be realized and attainedby the methods and systems particularly pointed out in the writtendescription and claims hereof, as well as from the appended drawings.

In accordance with an aspect of the disclosed subject matter, a methodis provided for coating a medical device including a body having anouter surface. For example, the medical device is a drug deliveryballoon or a balloon catheter. The method includes selecting acytostatic therapeutic agent, selecting at least one excipient, andblending the cytostatic agent and excipient to define a coating. In oneembodiment, the cytostatic therapeutic agent and at least one excipienthas a weight ratio of about 20:1 to about 1:20, and defines a coating,which provides increased efficiency of therapeutic transfer to a bodylumen. In another embodiment, the cytostatic therapeutic agent andpolymeric excipient define a coating in which at least one polymericexcipient has a polydispersity index from about 1.05 to about 10, andprovides increased efficiency of therapeutic transfer to a body lumen.

The method can include adding or blending a plasticizer with thecytostatic therapeutic agent and the excipient. For example, but notlimitation, the plasticizer includes glycerol. In one embodiment, theexcipient to plasticizer weight ratio is from about 20:1 to about 1:20and the cytostatic therapeutic agent and the at least one excipient havea weight ratio of about 20:1 to about 1:20.

In another embodiment, the medical device is a drug delivery balloonhaving a coating tuned to have a dissolution rate of about 10 seconds toabout 1 h. For the therapeutic agent, delivery with balloon inflationoccurs in less than 60 seconds and preferably less than 30 seconds.

In yet another aspect of the disclosed subject matter, a method isprovided for tuning the solubility of a coating for application to amedical device. In one embodiment, the excipient is modified prior toblending the cytostatic therapeutic agent and excipient to achievedesired delivery kinetics. In one embodiment, the excipient is modifiedby positively charging the excipient. In another embodiment, theexcipient includes a cyclic and aliphatic carbon chain and the excipientis modified by adjusting the ratio of cyclic chain to aliphatic chain.Advantageously, the adjusted chain ratio results in reduced elasticityand/or reduced release rate of the therapeutic agent. For example butnot limitation, the excipient can be poly(vinylpyrrolidone),poly(ethylene glycol), or poly(ester amide) polymer.

The excipient can be modified by grafting a low molecular weightpolyethylene glycol molecule to the excipient. In this regard, themodified excipient exhibits increased adhesion to a vessel wall. Inanother embodiment, the excipient is modified by increasing thecrystallinity of the excipient. For example and not limitation, theexcipient is poly(L-lactide-co-caprolactone) polyester, and thecrystallinity of the excipient is modified by adjusting the content ofL-lactide. In this regard, the content of L-lactide can be increased,thereby defining a coating having greater storage stability

The coatings of the disclosed subject matter can be applied to anysurface of the medical device. In one embodiment, it is applied to theouter surface of the medical device. In accordance with one embodiment,the coating is applied to the surface of the medical device by directfluid application. The method can further include applying heat to thecoated medical device to dry the coating.

It is to be understood that both the foregoing description is exemplaryand is intended to provide further explanation of the disclosed subjectmatter claimed to a person of ordinary skill in the art. Theaccompanying drawings are included to illustrate various embodiments ofthe disclosed subject matter to provide a further understanding of thedisclosed subject matter. The exemplified embodiments of the disclosedsubject matter are not intended to limit the scope of the claims.

BRIEF DESCRIPTION OF DRAWINGS

The disclosed subject matter will now be described in conjunction withthe accompanying drawings in which:

FIG. 1A depicts a representative planar view of a medical device of thedisclosed subject matter, which is shown as a balloon catheter forillustration and not limitation.

FIG. 1B is a cross-sectional view taken along lines A-A in FIG. 1A inaccordance with one embodiment of the disclosed subject matter.

FIG. 2 is a graph illustrating percent drug release as a function ofdrug, excipient and plasticizer ratio (D:E:P) in accordance with oneembodiment of the disclosed subject matter.

FIG. 3 are optical micrographs (100× magnification) demonstrating theresults of scratch tests of zotarolimus:PVP:glycerol coatings on glassslides at 10:1:0.4 (left panel) and 2:1:0.4 (right panel) in accordancewith one embodiment of the disclosed subject matter.

FIG. 4 are optical micrographs (100× magnification) demonstrating theresults of scratch tests of glass slide coatings ofzotarolimus:PVP:Tween 20, 2:1:0.67 (left panel) andzotarolimus:PVP:Tween 80, 2:1:0.4 (right panel) in accordance with oneembodiment of the disclosed subject matter.

FIG. 5 are optical micrographs (50× magnification) demonstrating theresults of scratch tests of glass slide coatings of zotarolimus:PEG-PE,2:1 (left panel) and zotarolimus:PEG-PE, 1:1 (right panel) in accordancewith one embodiment of the disclosed subject matter.

FIG. 6 are optical micrographs demonstrating the results of scratchtests of glass slide coatings of zotarolimus:PEG-PE, 1:2 underbrightfield (left panel, 50× magnification) or crossed polarizers (rightpanel, 200× magnification) in accordance with one embodiment of thedisclosed subject matter.

DETAILED DESCRIPTION

Reference will now be made in detail to the various aspects of thedisclosed subject matter. The method of the disclosed subject matterwill be described in conjunction with the detailed description of thedevice, the figures and examples provided herein.

As disclosed herein, the devices and methods presented can be used fordelivery within and/or treating of the lumen of a patient. Inparticular, the disclosed subject matter is particularly suited fortreatment of the cardiovascular system of a patient, such as performanceof angioplasty and delivery of a balloon expandable medical device, suchas a stent, filter and coil.

As disclosed herein, a balloon catheter is provided for delivery of atherapeutic agent, the balloon including an outer surface having atunable and durable coating disposed on at least a length of the outersurface. The tunable and durable coating includes a therapeutic agentand an excipient. The solubility of the coating in vivo, thebiosolubility, of the coating is tunable based on the substances andconcentrations chosen for the therapeutic agent and excipient

Referring to FIG. 1, for purposes of illustration and not limitation, anexemplary embodiment of balloon catheter device in accordance with thedisclosed subject matter is shown schematically in FIGS. 1A and 1B. Asdepicted in FIGS. 1A and 1B, the balloon catheter device 10 generallyincludes an elongated catheter shaft 12 having a proximal end and havinga distal end and an expandable balloon 30 located proximate to thedistal end of the catheter shaft. The expandable balloon has an outersurface and an inner surface disposed at the distal end portion of thecatheter shaft. In accordance with the disclosed subject matter, atunable coating 40 is applied to at least one length of the ballooncatheter, the tunable coating including a first therapeutic agent and afirst excipient, and can include a second therapeutic agent and a secondexcipient, wherein the first and second therapeutic agents havedifferent dissolution rates during balloon inflation. In accordance witha preferred embodiment, as illustrated by way of example and notlimitation in FIG. 1A, the coating is applied to at least one length ofthe outer surface of the balloon catheter.

The elongated catheter shaft 12 comprises an outer tubular member 14 andan inner tubular member 16. The outer tubular member 14 defines aninflation lumen 20 that can be disposed between the proximal end portionand the distal end portion of the catheter shaft 12. Specifically, asillustrated in FIG. 1B, the coaxial relationship between the innertubular member 16 and the outer tubular member 14 defines an annularinflation lumen 20. The expandable member 30 is placed in fluidcommunication with the inflation lumen 20. The inflation lumen cansupply fluid under pressure, and establish negative pressure to theexpandable member. The expandable member 30 can thus be inflated anddeflated. The elongated catheter is sized and configured for deliverythrough a tortuous anatomy, and can further include a guidewire lumen 22that permits it to be delivered over a guidewire 18. As illustrated inFIG. 1B, the inner tubular member 16 defines the guidewire lumen 22 forthe guidewire 18. Although FIGS. 1A and 1B illustrate the guidewirelumen as having an over-the-wire (OTW) construction, the guidewire lumencan be configured as a rapid-exchange (RX) construction, as is wellknown in the art.

As disclosed herein, the coating is tunable with respect to itssolubility. Therefore, the drug delivery balloon is able to provide thedesired delivery kinetics as a result of its tunability. The choice ofexcipient is key in determining efficacy factors such as, retaining ofthe therapeutic agent during delivery, releasing of the therapeuticagent during deployment, minimizing systemic dosing, maximizing agentdelivery efficiency and therapeutic effect, and preventing particulategeneration and related thromboses, among other factors.

As used in accordance with the disclosed subject matter, “tunable”refers to the ability to be tuned or adjusted for desired functioning.Accordingly, a tunable coating refers to a coating that can be adjustedaccording to various parameter discussed herein.

As disclosed herein, the balloon includes a tunable coating thatcomprises a therapeutic agent and an excipient. In accordance with oneembodiment, the tunable coating includes a first therapeutic agent and afirst excipient, and a second therapeutic agent and a second excipient.The coating has a biosolubility that is tunable based on the substancesand concentrations chosen for each of the therapeutic agent andexcipient. Preferably, the therapeutic agents have different dissolutionrates. The coating can include additional therapeutic agents andexcipients.

In accordance with the disclosed subject matter, the solubility of thecoating can be adjusted by modifying a number of factors, includingexcipient type, composition and molecular weight of the excipient,modulation of excipient or polymer properties such as aqueoussolubility, octanol/water partition coefficient, HLB(hydrophile-lipophile balance) number, glass transition temperature,degree of amorphous versus crystalline polymer, and orientation.Furthermore, the solubility or dissolution rates of the coating can beadjusted by varying the therapeutic agent concentration, therapeuticagent to excipient ratio, or coating thickness. Accordingly, thesefactors can be varied in order to provide a coating with the desiredsolubility and drug delivery kinetics.

The tunable coating provides for dissolution rates during ballooninflation that can be characterized generally as ranging from fast,soluble, intermediate, slow, extra slow, and non-soluble. Depending onthe target tissue or vasculature where the therapeutic agent is to bedelivered, the coating can be tuned such that the dissolution rateprovides for effective drug delivery and uptake. A “fast” coatingdissolution rate will typically have a dissolution time of less than 1minute. A “soluble” coating dissolution rate will typically have adissolution time ranging from about 1 minute to about 1 hour. An“intermediate” coating dissolution rate will typically have adissolution time ranging from about 1 hour to about 2 weeks. A “slow”coating dissolution rate will typically have a dissolution time rangingfrom about 2 weeks to about 3 months. An “extra slow” coatingdissolution rate will typically have a dissolution time ranging fromabout 3 months to 2 years. A “non-soluble” coating dissolution rate willtypically have a dissolution time greater than 2 years. However, itshall be noted that the specific dissolution of a coating composition isdependent upon an interplay between input factors and that thedissolution rates provided herein are, therefore, recited as ranges.

The excipients include various oil-based, biosoluble, and durable orbiodurable substances that are suitable for the delivery of atherapeutic agent. Biosolubility indicates solubility in a relevantbiological media, such as blood. A substance which is not intended todegrade in the body, or which degrades only very slowly, is biodurable.

In accordance with a preferred embodiment, the excipients of thedisclosed subject matter are water soluble. The excipients can includenon-ionic hydrophilic polymers. Non-ionic hydrophilic polymers include,but are not limited to, poly(vinyl pyrrolidone) (PVP, povidone),silk-elastin like polymer, poly(vinyl alcohol), poly(ethylene glycol)(PEG), pluronics (PEO-PPO-PEO), poly(vinyl acetate), poly(ethyleneoxide) (PEO), PVP-vinyl acetate (copovidone), polysorbate 80 (Tween 80),and polysorbate 20 (Tween 20). Preferably, the molecular weight ofnon-ionic hydrophilic polymers can be less than 50 kDa for fastsolubility. The excipient can also include fatty acids. Further, theexcipient can be a lubricious material which improves spreading anduniformity of coating.

In accordance with one embodiment, the excipient consists of abiocompatible plasticizer. Alternatively, the plasticizer can be addedto the excipient to keep it soft and pliable. Plasticizers can allow forgreater coating flexibility and elongation to prevent coating crackingduring inflation or brittleness. Plasticizers include, but are notlimited to, glycerol, ethanol, dimethylsulfoxide, ethyl lactate, benzylalcohol, benzyl benzoate, Cremophor EL, Vitamin E, tocopherol, liquidPEG (MW<1000), triethyl citrate, tributyl citrate, acetyl tributylcitrate, acetyl triethyl citrate, dibutyl phthalate, dibutyl sebacate,dimethyl phthalate, triacetin, propylene glycol, glycerin, 2-pyrridone,and combinations thereof. Preferably, a biocompatible plasticizer isused.

In accordance with yet another embodiment, sugars, polysaccharides orcellulosics, can be used as binders for the particles. Polysaccharidesinclude, but are not limited to, dextran, sulfonated dextran,hydrogenated dextran, chondroitin sulfate, sodium hyaluronate,hyaluronic acid, hyaluronan, chitosan, sodium alginate, sucrose, pectin,mannitol, carboxymethyl cellulose (CMC) sodium, methyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, andhydroxypropylmethylcellulose. Certain negative charged polysaccharideswill provide a mucoadhesive effect to enhance tissue drug retention.Furthermore, sugars such as mannitol will provide a decreasedhygroscopic effect when blended with more moisture-sensitive activeingredients such as cytostatic drugs or moisture sensitive excipients.Water soluble cellulosic materials can enhance coating strength orbrittleness.

In accordance with yet another embodiment, anti-coagulants can be usedas an excipient. For example, heparin based polysaccharides can providea minimally thrombogenic surface to prevent blood clotting on theballoon surface or minimize platelet activation induced by theprocedure. Heparin based polysaccharides include, but are not limitedto, heparin, heparin sulfate, heparin disaccharides, heparin fraction 1,heparin fraction 2, low molecular weight heparin, heparin ammonium,heparin calcium, heparin lithium, heparin lithium, and heparin zinclithium. Low molecular weight heparin includes centaxarin,periodate-oxidized heparin, heparin sodium end-amidated, heparin sodium,and nitrous acid delaminated.

In accordance with a preferred embodiment of the disclosed subjectmatter, the excipient possesses a mucoadhesive property. Thismucoadhesive property of the binder will lead to longer drug retentionwithin the coating adhered to the vessel wall. In particular, positivelycharged excipients such as chitosan, negatively charged excipients suchas some polysaccharides (e.g. carboxymethylcellulose, sodiumhyaluronate, sodium alginate) and some non-ionic hydrophilic polymersexhibit mucoadhesive properties. Any of the above carboxylated materialscan also be lightly activated with esters such as nitrophenolate orNHS-esters (N-hydroxy succinimide) for increased mucoadhesiveness.Alternatively, any above materials can be lightly thiolated forincreased mucoadhesiveness and continued solubility.

Additionally or alternatively, the excipient is or includes a contrastagent, including but not limited to, Iopromide (Ultravist), Ioxaglate(Hexabrix), Ioversol (Optiray), Iopamidol (Isovue), Diatrixoate(Conray), Iodixanol (Visipaque), Iohexol (Omnipaque), and Iotrolan. Atan intermediate coating thickness, a lower molecular weight (<1 kDa)hydrophilic contrast agent such as Iopromide (Ultravist) would enablefaster therapeutic release and a slightly higher viscous coating of thevessel wall as compared with drug alone. The contrast agents arelipophilic and can aid in drug uptake and retention into the tissuewall. In accordance with one embodiment, Ultravist and Optiray can beused given their more benign history of effects to smooth muscle andendothelial cells.

In accordance with yet another embodiment, excipients can consist ofcarboxylated aromatics similar in molecular structure to the structureused in contrast agents but without iodide substituents. Thesenegatively charged carboxylated aromatic structures can be alkylated(C2-C12) to optimize drug tissue uptake, or halogenated with fluoride,chloride or bromide for the same reason. The negatively chargedstructures are beneficial for tissue adhesiveness.

Table 1 provides non-limiting examples of the solubility data forexcipients that can be used in accordance with the disclosed subjectmatter:

TABLE 1 Solubility Enhancement of a Therapeutic Agent with SelectExcipients Zotarolimus Solubility Solution (5% w/w) (μg/ml, n = 3)Phosphate buffered saline 0.53 PVP C-17 5.6 ± 1.6Hydroxypropyl-β-cyclodextrin 11.6 ± 3.1  PEG 400 31.5 ± 3.5  Glycerol43.2 ± 30.1 5% γ-Cyclodextrin 55.3 ± 34.3 Vitamin E TPGS  512 ± 49.5Tween 20  732 ± 94.7 18:0 PEG2000 PE (PEG-PE)* 1020 ± 417 *1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000](ammonium salt)

As illustrated in Table 1, the excipients provide for increasedsolubility for the cytostatic drug, zotarolimus, as compared to salinealone. The excipients Vitamin E TPGS, Tween 20, and PEG-PE demonstratethe largest increase in zotarolimus solubility.

Table 2 provides non-limiting examples of coating dissolution ratesduring balloon inflation and representative excipient examples.

TABLE 2 Examples of Delivery Kinetics and Expected Variable Ranges forBalloon Coatings Coating Dissolution Rate (during Coating balloonDissolution Representative Excipient inflation) Time Example Fast <1minute Poly(vinylpyrrolidone) (PVP) (MW <60 kDa) or Poly(ethyleneglycol) (PEG) (lower MW <35 kDa) Soluble 1 min to 1 hourPoly(vinylpyrrolidone) (PVP) (MW >60 kDa) or Polyethylene oxide (PEO)(higher MW >100 kDa) Intermediate 1 hour to 2 weeks Silk-elastin likeprotein polymers Slow 2 weeks-3 months Biodegradable polymer such asPoly(D,L-lactide-co-glycolide) (PLGA) (50:50) Extra Slow 3 months-2years Biodegradable polymer such as Poly(L-lactide-co-ε-caprolactone)(PLLA:PCL) (70:30) Non-Soluble >2 years Durable polymer such asPoly(vinylidene fluoride-co- hexafluoropropylene)

As illustrated in Table 2 above, for a “fast” coating dissolution rate,representative excipient examples include, without limitation,polyvinylpyrrolidone (PVP) with a molecular weight less than about 60kDa, or polyethylene glycol (PEG) having a molecular weight less thanabout 35 kDa. The drug delivery mechanism and kinetics expected withthis representative example include the release of the therapeutic agentwith the coating during inflation. Further, the potential mucoadhesivepolymer increases drug retention time on tissue or vasculature.Alternatively, or additionally, the lipophilic additive increases druguptake in tissue.

As illustrated in Table 2 above, for a “soluble” coating dissolutionrate, representative excipient examples include, without limitation,poly(vinylpyrrolidone) (PVP) having a molecular weight greater thanabout 60 kDa, or poly(ethylene glycol) (PEG) having a molecular weightgreater than about 100 kDa. The drug delivery mechanism and kineticsexpected with this representative example are similar to that of the“fast” coating dissolution rate, however, the slightly slowerdissolution time allows for less drug wash off during balloon deliverybefore inflation.

As illustrated in Table 2 above, for an “intermediate” coatingdissolution rate, representative excipient examples include, withoutlimitation, silk-elastin like protein polymers. The drug deliverymechanism and kinetics expected with this representative exampleprovides for enhanced systemic drug loss protection and absence ofshort-term solubility, therefore allowing for enhanced particulatesafety. For an “intermediate” dissolution rate, the therapeutic agent isnot released together with the coating but from the coating. Thetherapeutic agent release kinetics and transfer to tissue aresignificantly enhanced by mechanical action during balloon inflation.Typically, these type of coating materials can by hydrophilic and canswell to some extent upon hydration to aid in fast drug release.

As illustrated in Table 2 above, for a “slow” coating dissolution rate,representative excipient examples include, without limitation,biodegradable polymers such as Poly(D,L-lactide-co-glycolide) (PLGA)(50:50). The coatings from biodegradable hydrophobic polymers will offerenhanced systemic drug loss protection and a better particulate safetyprofile. The therapeutic agent is not released together with the coatingbut from the coating. Drug release kinetics and transfer to tissue aresignificantly enhanced by mechanical action during balloon inflation.Techniques such as using a thin coating, a polymer with a low glasstransition temperature (Tg), and amorphous material or low crystallinematerial can provide for a more rapid drug release profile when using abiodegradable polymer.

As illustrated in Table 2 above, for an “extra slow” coating dissolutionrate, representative excipient examples include, without limitation,biodegradable polymers such as poly(L-lactide-co-ε-caprolactone)(PLLA:PCL) (70:30). The drug delivery mechanism and kinetics are similarto a “slow” coating dissolution rate, however the degradation time issignificantly extended. These coatings will have more long termdegradation and mechanical stability under storage.

As illustrated above, for a “non-soluble” coating dissolution rate,representative excipient examples include, without limitation, durablepolymers such as poly(vinylidene fluoride-co-hexafluoropropylene). Thedrug delivery mechanism and kinetics are similar to both a “slow” and“extra slow” coating dissolution rate, however the material isnon-biodegradable. These non-soluble coatings will have the mostchemical and mechanical stability under storage than other types.

In accordance with one embodiment, the excipient is a durable orbiodurable excipient. Certain representative examples of durableexcipients are provided in Table 3.

TABLE 3 Examples of durable excipients Excipient Specific DescriptionHydroxypropylmethylcellulose phthalate Coating agent, can improvecoating strength and be combined with plasticizer to reduce brittlenessPVP/PEO + acrylates + photoinitiator + PVP UV curable coating wouldretain drug during crosslinker delivery and rapidly release drug afterballoon expansion, lubricious Polyethylene vinyl acetate phthalateCoating agent, can improve coating strength and be combined withplasticizer to reduce brittleness Poly(ε-caprolactone) (PCL); flexiblematerial, low Tg and low crystallinity Poly (caprolactone)co-polymerized with material can provide for rapid drug release lactideand/or glycolide Poly(DL-lactide) Flexible material, soluble in varioussolvents for spray processing, can improve coating strength and becombined with plasticizer to reduce brittlenessPoly(L-lactide-co-e-caprolactone)(PLCL) Flexible material, soluble invarious solvents (50:50) for spray processing, can improve coatingstrength and be combined with plasticizer to reduce brittleness PCL-PEG(di and tri-block copolymers); Flexible material, can modulate PEGlength for Poly(trimethylenecarbonate) copolymerized varying degrees ofwater absorption and with caprolactone, lactide, glycolide and/orrelease rates other comonomoers; Poly(lactide)-PEG(di- and tri-blockcopolymers)lactide copolymerized with caprolactone, glycolide and/orother comonomers Polyethylene vinyl acetate Flexible material;biocompatible PVDF and PVDF copolymers (e.g., Solef) Blood compatible,low thrombogenicity, flexible materials with good temperature stability,soluble in acetone for spray processing PEA based on leucine, alanine,phenylalanine, Polymer structure can be fine tuned to any other aminoacid, or combinations thereof modulate drug miscibility and releaseprofile, soluble in various solvents for spray processingPhosphorylcholine derivatized polymers Non-thrombogenic polymerstructure that can including acrylates, methacrylates, PEA and be finetuned to modulate drug miscibility and aliphatic polyesters releaseprofile, soluble in various solvents for spray processing Silk-elastinlike polymers Thermally crosslinked, biocompatible PEG-based thol-enecrosslinked gels Enhanced mucoadhesiveness, low thrombogenicityPolyacrylic acid (Carbomer) Mucoadhesive, swells but does not dissolvein aqueous media PBMA copolymers; Good adhesion HPMA; PHEMA-co-PAAmHydrophilic polyurethane containing a PEO or Blood compatible, flexiblematerial, can other hydrophilic soft segment modulate water absorptionand drug release rate with soft segment MW and content

The durable excipients in accordance with the disclosed subject matterbind the therapeutic agent to the balloon or device surface and protectthe agent during delivery to a treatment location. For example, afterexpansion of the balloon at the treatment site, the balloon will contactthe vessel wall and the therapeutic agent will be rapidly released tocause the desired beneficial effect. During and after inflation, thebiodurable excipient will remain on the balloon with no particulateloss. To release the drug at a sufficient rate from these polymers, itis necessary to have high drug concentrations above perculation, withdrug to polymer ratios at about 1:1 or higher.

In accordance with one embodiment, a primer coating is necessary toallow for good and adequate adhesion such that, for example, a stent andcoating can be removed in a safe manner.

In accordance with the disclosed subject matter, the outer surface ofthe balloon has a tunable coating that is disposed on at least a lengthof the outer surface. Preferably, the tunable coating includes a firsttherapeutic agent and a first excipient and a second therapeutic agentand a second excipient. In accordance with a preferred embodiment, thefirst and second therapeutic agents have different dissolution ratesduring balloon inflation. Thus, the desired coating dissolution ratescan be tunable and achieved as desired for either drug kinetics orsafety profile. The delivery of the therapeutic agents can be modifiedand optimized to meet the therapeutic need. Furthermore, depending onthe excipients used, the therapeutic agents can be released from theexcipient or coating or with the excipient or coating. In accordancewith one embodiment, the first therapeutic agent is released from thecoating, and the second therapeutic agent is released with the coating.

In one embodiment, the first therapeutic agent is different than thesecond therapeutic agent. Alternatively, however, the therapeutic agentscan be the same.

In accordance with another embodiment, the coating can also include athird therapeutic agent and a third excipient. The therapeutic agentsand excipients can be applied simultaneously to the balloon surface orthey can be applied separately.

In accordance with yet another embodiment, the disclosed subject matterincludes a balloon having a the tunable coating including a cytostaticdrug and at least one excipient, wherein in the coating at least onepolymeric component has a polydispersity index from about 1.05 to about10, more preferably from 1.05 to 5. The polydispersity index (PDT), is ameasure of the distribution of molecular mass in a given polymer sample.The PDI calculated is the weight average molecular weight divided by thenumber average molecular weight. It indicates the distribution ofindividual molecular masses in a batch of polymers. A smaller PDI valueprovides a more consistent dissolution rate among the polymericexcipient molecules.

It has been found that coatings can be tunable to achieve desirabledissolution and drug delivery kinetics. In this regard, the choice of anexcipient or modified excipient can be important to define coatingsexhibiting efficacy factors such as but not limited to: how thetherapeutic agent is retained during delivery, how the agent is releasedduring balloon inflation, minimizing systemic drug dosing, maximizingagent delivery efficiency and therapeutic effect, and preventingparticulate loss, related thromboses and embolic events.

Accordingly, in one aspect of the disclosed subject matter, a method isprovided for coating a medical device, such as a drug coated balloon.The coating includes a cytostatic therapeutic agent and an excipienthaving a tunable molecular architecture. As used herein the phrase“tunable molecular architecture” means selection of an appropriateexcipient composition, molecular structure, functionality, andmorphology including appropriate modifications to yield the desiredcoating dissolution and drug delivery kinetics. The moleculararchitecture can be tuned through the design of input variables such asmonomer/polymer composition, aromaticity, hydrophilicity, molecularcharge, neutrality, aliphatic chain length, density of functionalgroups, molecular weight, aqueous solubility, octanol/water partitioncoefficient, HLB number, glass transition temperature, and percentcrystallinity. The method of the disclosed subject matter advantageouslyis capable of providing desired delivery kinetics as a result of itstunability.

In accordance with the disclosed subject matter, the method includesselecting a cytostatic therapeutic agent and an excipient, and blendingor mixing the cytostatic agent and excipient to define a coating. Themethod can further include tuning the molecular structure of the coatingsuch that specific characteristics of the coating that are important toproduct performance can be adjusted and optimized. Some of thesecharacteristics include coating solubility, coating hydrophilicity,coating adhesion and cohesion, coating stability under sterilization andstorage, drug release kinetics, drug solubility and stability, andsafety profile including particulate hazard and re-endothelialization.

For example and not limitation, the molecular architecture of theexcipient can be modified and tuned through the adjustment of severalinput parameters, as described in Table 4 below.

TABLE 4 Inputs that Affect Molecular Architecture and Excipient orCoating Characteristics Excipient Effect(s) of Effect(s) of ModificationIncrease Decrease Example Monomer/Polymer Choice of excipient or coatingcomposition Poly(vinylpyrrolidone) Composition has a large effect on allcoating characteristics. (PVP) or contrast agent for soluble coatingagent. Thin poly(vinylidene fluoride-co- hexafluoropropylene) (PVDF-HFP)for durable coating. Monomer/Polymer A high interaction between Morespacing between chains Increased L-lactide content Composition - polymerchains can provide can provide more amorphous in poly(L-lactide-co-Intramolecular for increased coating content and lower caprolactone)copolymers attraction: H mechanical stability, crystallinity for fastercan lead to higher Bonding versus cohesion, higher solubility anddecreased crystallinity. Polyurethane Steric Hindrance crystallinity andgreater stability of material. ureas exhibit increased H- molecularpacking density. bonding and mechanical stability. Hydrophilicity Willprovide faster water Slower water absorption, Non-ionic hydrophilicabsorption, faster drug release, slower drug release, and polymers suchas PVP and and faster coating dissolution. slower coating dissolution.polyethylene glycol (PEG) are water soluble and provide for fast coatingdissolution and drug delivery. Can increase or decrease PEG content as asoft segment in polyurethanes to increase or decrease hydrophilicity.Non-ionic hydrophobic polymers such as PVDF- HFP or PCL are non-watersoluble. Molecular Charge Charged molecules tend to Lower charge or moreneutral Charged polysaccharides or Neutrality possess mucoadhesivespecies can exhibit less such as carboxymethylcellulose, properties.mucoadhesive properties. sodium hyaluronate, chitosan, and sodiumalginate can exhibit mucoadhesive properties as well as complex and/orphysically bind negatively charged molecules. Cyclic Chain Cyclic chainwill increase Lower chain rigidity (lower Adjusting the ratio of cyclicchain rigidity (higher Tg), faster release rate and to aliphatic chainin Tg), therefore slow down higher % elongation. poly(ester amide) (PEA)the release rate. The polymers. elasticity will also be reduced as aresult. Aliphatic Chain Increased carbon chain Decreased carbon chainAdjusting length of Length length will lend towards lengths will lendtowards hydrocarbon chains in increased flexibility increased stiffness(higher poly(ester amide) (PEA) (lower Tg) of material for Tg) ofmaterial for lower polymers. higher % elongation and % elongation andfaster drug slower drug release. release. Density of Increase density ofLower density of functional RGD grafted low MW PEG Functional Groupsgrafted signaling or other groups and attached ligands can provide forincreased molecules such as RGD can allow for decreased adhesion ofreleased coating sequences for cell steric hindrance and to the vascularendothelial attachment. increased bioavailability. cell wall. MolecularWeight Higher molecular weight Lower molecular weight will Lowermolecular weight material will tend towards tend towards lower spray(<60 kDa). higher spray viscosity and viscosity and increasedpoly(vinylpyrrolidone) is lower solubility in solubility in variousspray easily spray coated due to various spray solvents and solvents andin aqueous its low spray viscosity and in aqueous media. In media. LowerMw will also high solubility in aqueous general, a higher translate tofaster release and organic media. molecular weight for rate. provide forincreased mechanical strength and cohesion of a coating to a certaincut-off value. Higher MW will also translate to slower release rate.Glass Transition Increased EtO Decreased EtO Certain low Tg Poly(e-Temperature sterilization stability sterilization stabilitycaprolactone) based and slower drug leading to coating flow andmaterials can provide a very release. Less flexible faster drug release.More fast burst release of drug up coating for decreased flexiblecoating for enhanced to 99%+ release at 1 day. handling and cathetercatheter processing Adding a plasticizer such as processing performance.performance. glycerol to non-ionic hydrophilic polymers such aspoly(vinylpyrrolidone) can lower the dry coating Tg to increase coatingflexibility. % Crystallinity Higher storage stability, Lower storagestability, Increasing or decreasing L- slower drug release, less fastersolubility, faster lactide) content in poly(L- flexible coating. drugrelease, more lactide-co-caprolactone) flexible coating. polyestercopolymers. Adding HFP to PVDF copolymer to increase coating flexibilityand drug release.

In accordance with the disclosed subject matter, the coating can beapplied to the medical device by processes such as dip-coating, pipettecoating, syringe coating, air assisted spraying, electrostatic spraying,piezoelectric spraying, spray drying, pneumatic spray, ultrasonic spray,spray with patterning, electrospinning, direct fluid application, orother means as known to those skilled in the art. The coating can beapplied over at least a length or the entirety of the balloon or medicaldevice. By way of example, and not limitation, certain coating processesthat can be used with the instant disclosed subject matter are describedin U.S. Pat. No. 6,669,980 to Hansen; U.S. Pat. No. 7,241,344 toWorsham; and U.S. Publication No. 20040234748 to Stenzel, the entiredisclosures of which are hereby incorporated by reference. In accordancewith one embodiment of the disclosed subject matter, the medical deviceis a balloon catheter and the coating can be applied to either a foldedor inflated balloon. Furthermore, the coating can be directly appliedinto the folds of the folded balloons. The coating characteristics areaffected by process variables. For example, for dip-coating process,coating quality and thickness can vary as an effect of variables such asnumber, rate, and depth of dips along with drying time and temperature.

In accordance with one embodiment, the balloon can be sprayed withtherapeutic agent encapsulated in the durable excipient solution. Spraysolvents can consist of the following class III solvents including butnot limited to acetone, anisole, 1-butanol, 2-butanol, butyl acetate,tert-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethylacetate, ethyl ether, ethyl formate, heptane, hexane, cyclohexane,isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol,methylethyl ketone, methylisobutyl ketone,cyclohexanone,2-methyl-1-propanol, pentanel, 1-pentanol, 1-propanol, and propylacetate, or blends thereof.

Additional spray solvents that can be used or blended with class IIIsolvents include class II spray solvents. The class II spray solventsinclude but are not limited to, acetonitrile, chloroform,1,2-dichloroethane, dichloromethane, 1,2-dimethyloxyethene,N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane,2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol,2-methoxyethanol, methyl butyl ketone, methylcyclohexane,N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran,tetralin, toluene, 1,1,2-trichloroethene, and xylene.

In accordance with the disclosed subject matter, the excipient andtherapeutic agent coating process can occur aseptically or be followedwith terminal sterilization methods such as E-beam, gamma irradiation,or ethylene oxide sterilization.

In accordance with the disclosed subject matter, excipients are utilizedtogether with the therapeutic agent in the coating at ratios rangingfrom 1:20 to 20:1 excipient:drug by weight, preferably from 1:10 to10:1, more preferably from 1:2 to 2:1. Preferably, the coating includesa plasticizer. In this regards, the excipient to plasticizer weightratio is from about 20:1 to about 1:20, more preferably from 10:1 to1:1.

In accordance with another embodiment of the disclosed subject matter,the coating includes various layers. In one embodiment, the coatingincludes first and second layers adsorbed to the surface of the balloon.The first layer typically consists of one therapeutic agent and oneexcipient and the second layer typically consists of a secondtherapeutic agent and second excipient. The drug coated balloon isdesigned such that the first and second layers each have a dissolutionrate. Preferably, the dissolution profile of the first layer isdifferent than the dissolution profile of the second layer. Providinglayers with various dissolution profiles allows the coating to be tunedto an optimized range.

In accordance with yet another embodiment, the disclosed subject matterincludes a method of increasing the efficiency of therapeutic transferto a body lumen by implanting or inserting a medical device in a bodylumen. The medical device includes an expandable member having an outersurface and a coating disposed on the outer surface of the medicaldevice, the coating including a therapeutic agent and an excipient.

For example and not limitation, the therapeutic agent or drug caninclude anti-proliferative, anti-inflammatory, antineoplastic,antiplatelet, anti-coagulant, anti-fibrin, antithrombotic, antimitotic,antibiotic, antiallergic and antioxidant compounds. Thus, thetherapeutic agent can be, again without limitation, a syntheticinorganic or organic compound, a protein, a peptide, a polysaccharidesand other sugars, a lipid, DNA and RNA nucleic acid sequences, anantisense oligonucleotide, an antibody, a receptor ligands, an enzyme,an adhesion peptide, a blood clot agent including streptokinase andtissue plasminogen activator, an antigen, a hormone, a growth factor, aribozyme, and a retroviral vector. Preferably, however, the therapeuticagents include a cytostatic drug. The term “cytostatic” as used hereinmeans a drug that mitigates cell proliferation, allows cell migration,and does not induce cell toxicity. These cytostatic drugs, include forthe purpose of illustration and without limitation, macrolideantibiotics, rapamycin, everolimus, zotarolimus, biolimus, novolimus,myolimus, temsirolimus, deforolimus, structural derivatives andfunctional analogues of rapamycin, structural derivatives and functionalanalogues of everolimus, structural derivatives and functional analoguesof zotarolimus and any macrolide immunosuppressive drugs. The term“antiproliferative” as used herein means a drug used to inhibit cellgrowth, such as chemotherapeutic drugs. Some non-limiting examples ofantiproliferative drugs include taxanes, paclitaxel, and protaxel.

Therefore, in accordance with a preferred embodiment, a balloon fordelivery of a cytostatic drug is provided. The outer surface of theballoon includes a tunable coating, the tunable coating including afirst cytostatic drug and a first excipient and a second cytostatic drugand a second excipient. The first and second cytostatic drugs preferablyhave different dissolution rates during balloon inflation. The variousdissolution rates allow for more effective and efficient delivery of thetherapeutic agent.

With reference to the balloon construction, a polymeric expandableballoon material is preferred. For example, the polymeric materialutilized to form the balloon body can be compliant, non-compliant orsemi-compliant polymeric material or polymeric blends.

In one embodiment, the polymeric material is compliant such as but notlimited to a polyamide/polyether block copolymer (commonly referred toas PEBA or polyether-block-amide). Preferably, the polyamide andpolyether segments of the block copolymers can be linked through amideor ester linkages. The polyamide block can be selected from variousaliphatic or aromatic polyamides known in the art. Preferably, thepolyamide is aliphatic. Some non-limiting examples include nylon 12,nylon 11, nylon 9, nylon 6, nylon 6/12, nylon 6/11, nylon 619, and nylon6/6. Preferably, the polyamide is nylon 12. The polyether block can beselected from various polyethers known in the art. Some non-limitingexamples of polyether segments include poly(tetramethylene ether),tetramethylene ether, polyethylene glycol, polypropylene glycol,poly(pentamethylene ether) and poly(hexamethylene ether). Commerciallyavailable PEBA material can also be utilized such as for example, PEBAX®materials supplied by Arkema (France). Various techniques for forming aballoon from polyamide/polyether block copolymer is known in the art.One such example is disclosed in U.S. Pat. No. 6,406,457 to Wang, thedisclosure of which is incorporated by reference.

In another embodiment, the balloon material is formed from polyamides.Preferably, the polyamide has substantial tensile strength, be resistantto pin-holing even after folding and unfolding, and be generally scratchresistant, such as those disclosed in U.S. Pat. No. 6,500,148 toPinchuk, the disclosure of which is incorporated herein by reference.Some non-limiting examples of polyamide materials suitable for theballoon include nylon 12, nylon 11, nylon 9, nylon 69 and nylon 66.Preferably, the polyamide is nylon 12. Other suitable materials forconstructing non-compliant balloons are polyesters such as polyethyleneterephthalate) (PET), Hytrel thermoplastic polyester, and polyethylene.

In another embodiment, the balloon is formed of a polyurethane material,such as TECOTHANE® (Thermedics). TECOTHANE® is a thermoplastic,aromatic, polyether polyurethane synthesized from methylene disocyanate(MDI), polytetramethylene ether glycol (PTMEG) and 1,4 butanediol chainextender. TECOTHANE® grade 1065D is presently preferred, and has a Shoredurometer of 65D, an elongation at break of about 300%, and a hightensile strength at yield of about 10,000 psi. However, other suitablegrades can be used, including TECOTHANE® 1075D, having a Shore Dhardness of 75. Other suitable compliant polymeric materials includeENGAGE® (DuPont Dow Elastomers (an ethylene alpha-olefin polymer) andEXACT® (Exxon Chemical), both of which are thermoplastic polymers. Othersuitable compliant materials include, but are not limited to,elastomeric silicones, latexes, and urethanes.

The compliant material can be cross linked or uncrosslinked, dependingupon the balloon material and characteristics required for a particularapplication. The presently preferred polyurethane balloon materials arenot crosslinked. However, other suitable materials, such as thepolyolefinic polymers ENGAGE® and EXACT®, are preferably crosslinked. Bycrosslinking the balloon compliant material, the final inflated balloonsize can be controlled. Conventional crosslinking techniques can be usedincluding thermal treatment and E-beam exposure. After crosslinking,initial pressurization, expansion, and preshrinking, the balloon willthereafter expand in a controlled manner to a reproducible diameter inresponse to a given inflation pressure, and thereby avoid overexpandingthe stent (if used in a stent delivery system) to an undesirably largediameter.

In one embodiment, the balloon is formed from a low tensile set polymersuch as a silicone-polyurethane copolymer. Preferably, thesilicone-polyurethane is an ether urethane and more specifically analiphatic ether urethane such as PURSIL AL 575A and PURSIL AL10,(Polymer Technology Group), and ELAST-EON 3-70A, (Elastomedics), whichare silicone polyether urethane copolymers, and more specifically,aliphatic ether urethane cosiloxanes. In an alternative embodiment, thelow tensile set polymer is a diene polymer. A variety of suitable dienepolymers can be used such as, but not limited to, an isoprene such as anAB and ABA poly(styrene-block-isoprene), a neoprene, an AB and ABApoly(styrene-block-butadiene) such as styrene butadiene styrene (SBS)and styrene butadiene rubber (SBR), and 1,4-polybutadiene. Preferably,the diene polymer is an isoprene including isoprene copolymers andisoprene block copolymers such as poly(styrene-block-isoprene). Apresently preferred isoprene is a styrene-isoprene-styrene blockcopolymer, such as Kraton 1161K available from Kraton, Inc. However, avariety of suitable isoprenes can be used including HT 200 availablefrom Apex Medical, Kraton R 310 available from Kraton, and isoprene(i.e., 2-methyl-1,3-butadiene) available from Dupont Elastomers.Neoprene grades useful in the disclosed subject matter include HT 501available from Apex Medical, and neoprene (i.e., polychloroprene)available from Dupont Elastomers, including Neoprene G, W, T and A typesavailable from Dupont Elastomers.

In accordance with another aspect of the disclosed subject matter, theouter surface of the balloon is modified. In this regard, the balloonsurface can include a textured surface, roughened surface, voids,spines, channels, dimples, pores, or microcapsules or a combinationthereof, as will be described below.

In accordance with the disclosed subject matter, the balloon does notinclude a stent or is free of a stent. However, a stent can be mountedonto the coated balloon. The stent will not detrimentally affect coatingintegrity or drug delivery. The type of stent that can be used includes,but is not limited to, bare metal stent, balloon expandable stent, selfexpanding stent, drug eluting stent, prohealing stent, andself-expanding vulnerable plaque implant. The balloon can be coatedindependently of the stent or in conjunction with the stent coatingprocess. The stent coating can contain the same or different therapeuticagents from the balloon catheter or expandable member. However, theparticular coating on the balloon catheter or expandable memberpreferably has distinct release kinetics from the therapeutic coating onthe stent.

In one embodiment of the disclosed subject matter, the balloon is formedof a porous elastomeric material having at least one void formed in thewall of the balloon surface. For example, the entire cross section ofthe balloon can contain a plurality of voids. Alternatively, theplurality of void can be distributed along select lengths of the balloonouter surface. For example and not limitation, the plurality of voidscan be distributed only along only the working section of the balloon.The voids define an open space within the outer surface of the balloon.Preferably, the therapeutic agent is dispersed within the space definedby the plurality of voids across the cross section of the balloon outersurface.

In operation, the therapeutic agent is released or is expelled from thepores upon inflation of the balloon. In this regard, the durometer ofthe polymeric material of the balloon surface and in particular thedepression of the void is sufficiently flexible to allow for expulsionof the therapeutic agent and/or coating contained within the pluralityof voids upon inflation of the balloon. The expelled coating withtherapeutic agent is released into the vessel lumen or into the tissuesurrounding and contacting the inflated balloon.

In another embodiment, the balloon includes protrusions configured tocontact or penetrate the arterial wall of a vessel upon inflation of theballoon. A coating containing therapeutic agent is disposed on theprotrusions and when inflated the coating and/or therapeutic agent coatsthe tissue of the arterial wall. Alternatively, the balloon can includetwo concentric balloons in a nesting configuration. The coating withtherapeutic agent is disposed between the two concentric balloons. Thus,the space between the two concentric balloons; one being an interiorballoon and the other being an exterior balloon, acts as a reservoir. Inthis regard, the protrusions can include apertures for expulsion of thecoating and/or therapeutic agent upon inflation of the interior andexterior concentric balloons. For example, as described in U.S. Pat. No.6,991,617 to Hektner, the disclosure of which is incorporated herein byreference thereto. In another embodiment, the balloon can includelongitudinal protrusions configured to form ridges on the balloonsurface. As described in U.S. Pat. No. 7,273,417 to Wang, the entiredisclosure of which is incorporated herein by reference, the ridges canbe formed of filaments spaced equidistantly apart around thecircumference of the balloon. However, a larger or smaller number ofridges can alternatively be used. The longitudinal ridges can be fullyor partially enveloped by the polymeric material of the balloon.

In yet another embodiment of the disclosed subject matter, the ballooncan include microcapsules on its outer surface. In this regard, themicrocapsules are configured to encompass the coating and/or therapeuticagent. Upon inflation of the balloon the microcapsules located on thesurface of the balloon contact the tissue of the arterial wall.Alternatively, the microcapsules can be formed in the wall of theballoon surface. The coating and/or therapeutic agent can be releasedfrom the microcapsules by fracturing of the microcapsules and/ordiffusion from the microcapsule into the arterial wall. Themicrocapsules can be fabricated in accordance with the methods disclosedin U.S. Pat. No. 5,1023,402 to Dror or U.S. Pat. No. 6,129,705 to Grantzand the patents referenced therein, each of which is incorporated hereinby reference in its entirety.

In accordance with another aspect of the disclosed subject matter, ifdesired, a protective sheath can be utilized to protect the coating frombeing rubbed off of the balloon during the movement of the coatedballoon through the body lumen. The sheath is preferably made from anelastic and resilient material which conforms to the shape of theballoon and in particular is capable of expanding upon inflation of theballoon. The sheath preferably includes apertures along a lengththereof. In operation, the inflation of the balloon causes the aperturesof the sheath to widen for release of the coating and/or therapeuticagent to the tissue of the arterial wall. Preferably, the sheath has athickness less than 10 mils. However, other thicknesses are possible.

In another embodiment, the sheath has at least one longitudinal line ofweakness allowing the sheath to rupture upon inflation of the balloonand the release of the coating and/or therapeutic agent onto the tissueof the arterial wall of the vessel. Preferably, the sheath is formedfrom polymeric material known to be suitable for use in ballooncatheters. Preferably, the sheath material is an elastomeric materialwhich will also spring back when it splits to expose more of the bodylumen to the coating. The line of weakness could be provided by varioustechniques known in the art. However, one non-limiting examples includeperforating the sheath material. In operation, the sheath is placed overthe coated balloon while in the deflated state. When the coated balloonis inflated, the sheath is expanded to the extent that it exceeds itselastic limit at the line of weakness and bursts to expose and thereforerelease the coating and/or therapeutic agent to the tissue of thearterial wall or vessel lumen. For example, see U.S. Pat. No. 5,370,614to Amundson, the entire disclosure of which is incorporated byreference.

In accordance with another embodiment, an outer fibrous coating can beelectrospun or stretched onto the medical device or balloon catheter toprevent drug loss during delivery. During balloon inflation, the coatingis stretched and allows for coating dissolution and release. The fiberdiameters and material properties can be fine tuned for optimal poresize and to release the particles containing the therapeutic agent.Fibrous coatings on expandable members are described in U.S. patentapplication Ser. No. 12/237,998 to R. von Oepen and U.S. patentapplication Ser. No. 12/238,026 to K. Ehrenreich, the disclosures ofwhich are incorporated by reference in their entirety.

It is to be noted that the term “a” entity or “an” entity refers to oneor more of that entity. For example, a protein refers to one or moreproteins or at least one protein. As such, the terms “a”, “an”, “one ormore”, and “at least one” can be used interchangeably herein. The terms“comprising,” “including,” and “having” can also be usedinterchangeably. In addition, the terms “amount” and “level” are alsointerchangeable and can be used to describe a concentration or aspecific quantity. Furthermore, the term “selected from the groupconsisting of refers to one or more members of the group in the listthat follows, including mixtures (i.e. combinations) of two or moremembers.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 3 or more than 3 standard deviations,per the practice in the art. Alternatively, “about” can mean a range ofup to +1-20%, preferably up to +1-10%, more preferably up to +/−5%, andmore preferably still up to +/−1% of a given value. Alternatively,particularly with respect to biological systems or processes, the termcan mean within an order of magnitude, preferably within 5-fold, andmore preferably within 2-fold, of a value. With reference topharmaceutical compositions, the term “about” refers to a range that isacceptable for quality control standards of a product approved byregulatory authorities.

EXAMPLES

The present application is further described by means of the examples,presented below. The use of such examples is illustrative only and in noway limits the scope and meaning of the disclosed subject matter or ofany exemplified term.

Example A

To simulate drug release from a drug coated balloon, a three stepin-vitro release method was developed. This method consists of asequential dip release in 37° C. porcine serum for 1 min, inflationrelease in 37° C. porcine serum for 1 min and extraction release in 50%acetonitrile solution designed to mimic the balloon release duringdelivery to the lesion, drug delivery on inflation and the remainingdrug on the balloon respectively. The resulting zotarolimusconcentrations in the porcine serum supernatant are measured by liquidchromatography mass spectrometry (LCMS) and drug from the extractionmeasured by high performance liquid chromatography (HPLC).

This in-vitro release method was used to evaluate the drug release fromzotarolimus (Zot):poly(vinylpyrrolidone) (PVP):glycerol drug coatedballoons as a function of drug:excipient:plasticizer ratio (D:E:P) andPVP K-value. For the combined dip release and inflation release thatsimulates coating dissolution rate and drug delivery from a drug coatedballoon, it is shown in FIG. 2 that a higher drug to excipient ratiosuch as D:E:P, 20:1:0.4 (w/w) resulted in a “soluble” coatingdissolution rate with a dissolution time in the range of 1 min to 1 hreleasing less than 5% of drug in 2 min. For lower D:E:P ratios andincreasing amounts of plasticizer, the Zot:PVP:glycerol formulationdemonstrated a “fast” dissolution rate, i.e. less than 1 min releasingup to 90% of drug in 2 min. For a lower molecular weight or PVP K-valuesuch as PVP C-15, the coating dissolution rate and drug release duringthe dip release was further increased to 30% as compared to the PVP C-30coating at the same 1:1:0.4, D:E:P ratio which demonstrated less than 5%dip release. The K-Values of C-15 and C-30 designate PVP K value for lowendotoxin grade.

Example B

Scratch tests of coatings on glass slides were used to qualitativelyevaluate coating mechanical properties in terms of hardness andtackiness. FIGS. 3 through 6 are optical micrographs of drug deliveryballoon coating formulations coated onto glass slides. To produce theoptical micrographs, the coating formulations were pipetted onto glassslides, and then the slides were baked at 50° C. for one hour. Whileobserving under an optical microscope, the coatings were scratched witha steel mandrel to assess their hardness, brittleness, and resistance tofracture in the dry state. Stickiness was assessed by placing anotherclean glass slide onto the coatings, pressing them together and notingthe force, if any, required to pull them apart.

It was observed that increasing the drug to excipient ratio forzotarolimus:PVP:glycerol to 10:1:0.4 (FIG. 3 left panel) from 2:1:0.4(FIG. 3 right panel) resulted in increased hardness and reducedtackiness. Representative optical micrographs of these coatings afterscratching are shown in FIG. 3. Coating with the 10:1:0.4 ratio (leftpanel) is much harder than the 2:1;0.4 ratio (right panel), which waswaxy.

Example C

The qualitative mechanical properties of zotarolimus:PVP:tween 20coatings were evaluated by scratch tests of coatings deposited on glassslides. It was shown with representative optical micrographs in FIG. 4(left panel) that zotarolimus:PVP:tween 20 at a ratio of 2:1:0.67exhibited a soft and waxy coating. With zotarolimus:PVP:tween 80 at aratio of 2:1:0.4 as shown in FIG. 4 (right panel) a slightly brittle,weak and chunky coating resulted.

Example D

The qualitative mechanical properties of zotarolimus:PEG-PE coatingswere evaluated by scratch tests of coatings deposited on glass slides.It was shown with representative optical micrographs in FIG. 5 (leftpanel) that zotarolimus:PEG-PE, 2:1 exhibited a soft and waxy coating.With zotarolimus:PEG-PE, 1:1 as shown in FIG. 5 (right panel) a soft,waxy and tacky coating resulted. This coating underwent visible flowafter scratching. Zotarolimus:PEG-PE, 1:2 as shown in FIG. 6 (leftpanel) exhibited a hard and waxy coating and was birefringence whenobserved under polarized light (right panel). This drug:excipient systemexhibited eutectic behavior with the 1:1 ratio coating being the softestand compositions greater in either component being harder. Furthermore,at the lower drug:excipient ratio of 1:2 the birefringence indicatescrystallization of the PEG-PE component.

The disclosed subject matter can be embodied in other specific formswithout departing from its spirit or essential characteristics. Thedescribed embodiments are to be considered in all respects only asillustrative and not restrictive. Thus, it is intended that thedisclosed subject matter include modifications and variations that arewithin the scope of the appended claims and their equivalents. Allreferences recited herein are incorporated herein in their entirety byspecific reference.

1. A method of coating a medical device having an outer surface, themethod comprising: selecting a cytostatic therapeutic agent; selectingat least one excipient; blending the cytostatic agent and excipient todefine a coating; and applying the coating to the outer surface of themedical device, wherein the cytostatic therapeutic agent and the atleast one excipient have a weight ratio of about 20:1 to about 1:20, andfurther wherein the coating provides increased efficiency of therapeutictransfer to a body lumen.
 2. The method of claim 1, further including:blending a plasticizer with the cytostatic therapeutic agent and theexcipient.
 3. The method of claim 2, wherein the excipient toplasticizer weight ratio is from about 20:1 to about 1:20.
 4. The methodof claim 1, wherein the cytostatic therapeutic agent and the at leastone excipient has a weight ratio of about 2:1 to about 1:2.
 5. Themethod of claim 1, wherein the cytostatic therapeutic agent iszotarolimus.
 6. The method of claim 1, wherein the excipient ispoly(vinylpyrrolidone).
 7. The method of claim 2, wherein theplasticizer is glycerol.
 8. The method of claim 1, wherein the coatingis applied to the outer surface of the medical device by direct fluidapplication.
 9. The method of claim 1, further including applying heatto the coated medical device to dry the coating.
 10. The method of claim1, wherein the medical device is a balloon catheter.
 11. A method ofcoating a medical device having an outer surface, the method comprising:selecting a cytostatic therapeutic agent; selecting at least onepolymeric excipient; blending the cytostatic therapeutic agent and atleast one polymeric excipient to define a coating; and applying thecoating to at least one length of the outer surface of the medicaldevice, wherein the at least one polymeric excipient has apolydispersity index from about 1.05 to about 10 and provides increasedefficiency of therapeutic transfer to a body lumen.
 12. The method ofclaim 11, further including: blending a plasticizer with the cytostatictherapeutic agent and excipient.
 13. The method of claim 11, whereincytostatic therapeutic agent is zotarolimus.
 14. The method of claim 11,wherein the excipient is poly(vinylpyrrolidone).
 15. The method of claim12, wherein the plasticizer is glycerol.
 16. The method of claim 11,wherein the medical device is a balloon catheter.
 17. A method ofcoating a medical device having an outer surface, the method comprising:selecting a cytostatic therapeutic agent; selecting at least oneexcipient; blending the cytostatic therapeutic agent and at least oneexcipient to define a coating; applying the coating to at least onelength of the outer surface of the medical device; and inserting orimplanting the coated medical device in a body lumen, wherein thecoating has a dissolution rate of about 10 seconds to about 1 hour andprovides an increased efficiency of therapeutic transfer to a bodylumen.
 18. The method of claim 17, further including: blending aplasticizer with the cytostatic therapeutic agent and excipient.
 19. Themethod of claim 17, wherein cytostatic therapeutic agent is zotarolimus.20. The method of claim 17, wherein the excipient ispoly(vinylpyrrolidone).
 21. The method of claim 18, wherein theplasticizer is glycerol.
 22. The method of claim 17, wherein thetherapeutic transfer to the body lumen occurs in less than 5 minutes.23. The method of claim 17, wherein the therapeutic transfer to the bodylumen occurs in 30 seconds or less.
 24. The method of claim 17, whereinthe medical device is a balloon catheter
 25. A method of tuning thesolubility of a coating for a medical device, the method comprising:selecting a first cytostatic therapeutic agent; selecting a firstexcipient; blending the first cytostatic agent and the first excipientto define a first coating, the first coating having a first dissolutionrate; selecting a second cytostatic therapeutic agent; selecting asecond excipient; blending the second cytostatic agent and secondexcipient to define a second coating, the second coating having a seconddissolution rate; wherein the first and second dissolution rates aredifferent; and applying the first and second coatings to at least onelength of the outer surface of the medical device, the differentdissolution rates defining a tunable solubility.
 26. The method of claim25, wherein the first excipient is a polymer having a molecular weightof less than about 35 kDalton.
 27. The method of claim 25, wherein thesecond excipient is a polymer having a molecular weight greater thanabout 100 kDalton.
 28. The method of claim 25, wherein the firstexcipient is poly(vinylpyrrolidone) or poly(ethylene glycol).
 29. Themethod of claim 25, wherein the second excipient ispoly(vinylpyrrolidone) or poly(ethylene glycol).
 30. The method of claim25, wherein the medical device is a balloon catheter
 31. A method ofcoating a medical device, the method comprising: selecting a therapeuticagent; selecting at least one excipient; modifying the excipient;blending the therapeutic agent and the charged excipient to define acoating; and applying the modified excipient to an expandable member,wherein the coating provides desired delivery kinetics.
 32. The methodof claim 31, further including charging the excipient with a positivecharge.
 33. The method of claim 31, further including charging theexcipient with a negative charge.
 34. The method of claim 31, whereinthe excipient includes cyclic and aliphatic carbon chains, and furtherwherein the excipient is modified by adjusting cyclic chain to aliphaticchain ratio.
 35. The method of claim 34, wherein the adjusted ratioresults in reduced elasticity.
 36. The method of claim 34, wherein themodified excipient includes a therapeutic agent and further wherein theadjusted ratio results in reduced release rate of the therapeutic agent.37. The method of claim 31, wherein the excipient is poly(ester amide)polymer.
 38. The method of claim 31, wherein the excipient is modifiedby grafting a low molecular weight polyethylene glycol molecule to theexcipient, and further wherein modified excipient exhibits increasedadhesion to a vessel wall.
 39. The method of claim 31, wherein themodified excipient has increased crystallinity.
 40. The method of claim39, wherein the excipient is poly(L-lactide-co-caprolactone) polyester,and the crystallinity of the excipient is modified by adjusting thecontent of L-lactide.
 41. The method of claim 40, wherein the content ofL-lactide is increased and the excipient exhibits greater storagestability.
 42. The method of claim 31, wherein the coating is applied toa balloon.